[unreadable] Mitral regurgitation (MR) is a common complication of ischemic heart disease that increases mortality and promotes left ventricular (LV) remodeling and dysfunction. Effective repair remains elusive, and improved understanding of mechanism can suggest new approaches. Such MR is caused by an abnormal balance of forces acting on the valve: leaflet closure is restricted by unbalanced tethering to the displaced papillary muscles (PMs) and dilated annulus. Annular reduction alone is often ineffective because of persistent tethering to the LV wall. Disappointing results, prolonged bypass, and increased mortality can deter surgical repair. This proposal tests two complementary interventions that reduce tethering: adjustable PM repositioning by an external patch and inflatable balloon device, applied in the beating heart under echo guidance; and cutting or elongating selected basal chordae that most distort the leaflets and limit coaptation. These approaches have proved effective acutely and in long-term pilots of segmental dysfunction in sheep. The proposal will test the hypothesis that these interventions have long-term efficacy in reducing ischemic MR following myocardial infarction (MI). A corollary is that these approaches also attenuate or reverse LV remodeling, and are effective despite any continued remodeling. The spectrum of established models to be used includes a more localized inferior MI with displacement of the posterior or medial papillary muscle (PM), and a more extensive MI that involves both PMs. Interventions to prevent or reverse MR will be tested in each model, either shortly after infarction, or 8 weeks later with the development of remodeling and MR. For each model and time point, control animals will be compared with those receiving interventions to determine whether MR reduction is maintained, LV function is preserved, and remodeling is attenuated. Changes in MR will be analyzed in terms of tethering relationships by 3D echo reconstruction. Because chordal modification and annuloplasty deal with opposite ends of the tethering mechanism, they will be tested independently and in combination. The experimental design also explores under what circumstances interventions need to be combined in order to relieve tethering comprehensively at both the annular and papillary muscle ends. The overall goal is to provide a sound basis for more consistent and effective repair of ischemic MR to reduce this frequent stimulus to heart failure in patients. [unreadable] [unreadable]